Copper depletion therapy keeps high-risk triple-negative breast cancer at bay

An anticopper drug compound that disables the ability of bone marrow cells to set up a “home” in organs to receive and nurture migrating cancer tumor cells has shown surprising benefit in one of the most difficult-to-treat forms of cancer—high-risk triple-negative breast  cancer.

The median survival for patients with metastatic triple-negative breast cancer historically has been 9 months. In a high-risk subset of breast cancer patients, the risk of relapse is high—50% to 70% over 5 years for patients with stage III disease, and patients with stage IV disease always recur. Triple-negative breast cancer patients have a poorer prognosis even when the disease is diagnosed in early stages.

However, results of a new phase II clinical trial show that if patients at high-risk of relapse with no current visible breast cancer are copper depleted, the result is a prolonged period of time with no cancer recurrence. Only two of 11 study participants with a history of advanced triple-negative breast cancer relapsed within 10 months after using the anticopper drug, tetrathriomolybdate (TM).

TM is a copper chelation compound used to treat Wilson disease, a hereditary copper metabolism disorder. TM has been studied in phase I and phase II clinical trials for a number of disorders. Animal studies have demonstrated that depleting copper decreases proliferation of endothelial progenitor cells, as well as blood vessel formation and growth. Copper is critical to mobilizing cancer cells and is essential to the metastatic process. This is the first human clinical trial to deplete copper in breast cancer patients.

"These study findings are very promising and potentially a very exciting advance in our efforts to help women who are at the highest risk of recurrence," said the study's senior investigator, Linda Vahdat, MD, of Weill Cornell Medical College. She said that four of the study participants with a history of metastatic triple-negative breast cancer have had long-term benefit, remaining disease-free for between 3 and 5 years.

"The anticopper compound appears to be keeping tumors that want to spread in a dormant state," said Vahdat. "We believe one of the important ways it works is by affecting the tumor microenvironment, specifically the bone marrow-derived cells that are critical for metastasis progression."

In addition, study participants with other forms of breast cancer with a high-risk for relapse—either stage III or stage IV—without evidence of disease after treatment have also fared well. The progression-free survival rate among these 29 patients in the study has been 85%, to date.

"As good as these interim findings look to us, we cannot talk about significant benefit until we compare TM treatment to other therapies," she said. Vahdat expects to launch a phase III randomized clinical trial soon.

This research is a report of the first 40 patients, and it was published in Annals of Oncology (2013; doi:10.1093/annonc/mds654). The clinical trial, which began in 2007, has been expanded many times and now includes 60 patients, more than half of whom have triple-negative breast cancer.

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